Surgical method

ABSTRACT

This invention relates to the surgical use of monomeric esters of Alpha -cyanoacrylic acid having the formula   WHEREIN R is a saturated hydrocarbon radical of two to 10 carbon atoms for the purpose of bonding together living tissue.

United States Patent 1 Coover, Jr. et al;

[ Sept. 18, 1973 SURGICAL METHOD [73] Assignees Eastman Kodak Company,

Rochester, N.Y.

22 Filed: Apr. 7, 1966 211 App]. No; 541,026

[52] U.S. Cl. 128/334 R, 260/78.4 N

[51] Int. Cl A6lb 17/04 [58] Field of Search 128/334 R, 156; 260/78.4 N

[56] References Cited UNITED STATES PATENTS 2,765,332 10/1956 Coover etal. 260/784 N 2,794,788 6/1957 Coover et al. 260/78.4 N

3,223,083 12/1965 Cobey 128/92 3,667,472 6/1972 Halpern 128/334 R OTHERPUBLICATIONS Carton et aL, Surg. Foruin l 1:236 9 1960: I

Nathan et aL, Annals of Surgery" Vol. 152, No. 4, 1960, pages 648-659.

Kessler Surgical Forum 11:403-4, 1960.

Primary Examiner-Dalton L. Truluck AttorneyR. Frank Smith and William T.French [57] ABSTRACT This invention relates to the surgical use ofmonomeric esters of a-cyanoacrylic acid having the formula CN /0 caps-owherein R is a saturated hydrocarbon radical of two to 10 carbon atomsfor the purpose of bonding together living tissue.

12 Claims, No Drawings SURGICAL METHOD This invention relates to a newuse for esters of u-cyanoacrylic acid and more particularly to asurgical method for joining tissue surfaces through the use of suchesters as adhesives.

The usual methods for closing incisions in flesh and for setting bonefractures, by the use of sutures, clamps, pins or the like, have manydrawbacks. The use of an adhesive substance for these surgical purposeswould have the advantage of permitting rapid joining of the damagedmembers and of permitting natural healing. However, the common adhesivesare unsuitable for surgical use. Most adhesives need too much time toform a bond. Many require the use of heat or pressure or the evaporationof a solvent, all of which make them unsuitable as surgical. adhesives.Other adhesives, including some that might otherwise be suitable forsurgical use, are excessively irritating to the body tissues.

References are found in the literature to the use of methyla-cyanoacrylate as a bone cement or as a suturing material. In such usethe methyl a-cyanoacrylate polymerizes in situ without the use of heator pressure or the evaporation of a solvent. in many respects it is thussuperior to conventional adhesives for surgical use. However, the use ofmethyl a-cyanoacrylate as a surgical adhesive has had somedisadvantages. For one thing, the bonds that it forms are often toobrittle for surgical purposes. Further, the methyl ester ofa-cyanoacrylic acid is not consistently successful in forming a bond inliving tissues, especially when there is oozing of blood or otherfluids. Still further, commercial formulations of methyl a-cyanoacrylatehave caused some unexplained side reactions.

The present invention is based on our discovery that certain higheresters of a-cyanoacrylic acid are unexpectedly superior to methyla-cyanoacrylate as surgical adhesives and are free of disadvantages thathave been encountered in surgical uses of the methyl ester.

The esters of a-cyanoacrylic acid (also designated as 2-cyanoacrylicacid) which are effective in the method of the invention can berepresented by the formula:

wherein R is a saturated hydrocarbon radical of 2 to carbon atoms.

In accordance with the invention we have found that these esters aremarkedly superior to methyl 2- cyanoacrylate as surgical adhesives. Thebonds that they form are more flexible than those of the methyl ester.in normal surgical use they do not evolve the pungent irritating vaporthat characterizes the methyl ester. They have greater hydrolyticstability than the methyl ester, a property of considerable value inview of the fact that in normal use a surgical adhesive can be expectedto be in contact with moisture. They form reasonably rapid bonds andthey are more consistent than the methyl ester in forming firm closuresof flesh incisions, particularly when seepage of blood or other fluidscreates difficulties.

The a-cyanoacrylate esters that we use are esters of saturated aliphaticalcohols, by which we mean open chain or alicyclic alcohols, having 2 to10 carbon atoms, those having 3 to 6 carbon atoms being particularlysuitable. Examples include esters in which R of the above formula is asaturated hydrocarbon radical such as ethyl, propyl, isopropyl, n-butyl,isobutyl, amyl, isoamyl, capryl, cyclopentyl, cyclohexyl, 2-ethylhexyl,etc. Preferred as surgical adhesives are the esters of branched alkanolshaving a single alkyl side chain, i.e., esters of the above formula inwhich R is a singly branched chain alkyl radical. Among their other goodproperties such esters and their polymeric bonds are less sensitive towater than the methyl ester. Especially preferred among such esters isthe isobutyl ester. The isobutyl ester is outstanding in forming rapidlya flexible bond of adequate strength for surgical purposes. It has verylittle odor. it is soluble in ethanol, which makes it easy to removefrom tissues when necessary.

The a-cyanoacrylate esters can be produced by the procedure of thepatent to Joyner and Hawkins, U.S. Pat. No. 2,721,858, involvingreaction of an alkyl cyanoacetate with formaldehyde in a non-aqueousorganic solvent and in the presence of a basic catalyst, followed bypyrolysis of the anhydrous intermediate polymer in the presence ofpolymerization inhibitor. The a-cyanoacrylate monomers prepared with lowmoisture content and essentially free of impurities have the bestactivity for surgical use. A preferred method for preparing suchmonomers is described in Belgian Pat. No. 611,273.

The indicated esters of a-cyanoacrylic acid polymerize from the liquidto the solid state by an anionic polymerization mechanism and have amarked affinity for adhering to surfaces of living tissue. The cause forthis affinity is not certain but it is believed that the highly polarnature of the ester molecule is responsible because the living skin,bone and other tissues are known to be polar. Since the polymerizationof these monomeric esters is initiated by an anionic attack, thepolymerization is accelerated somewhat when the monomer comes intocontact with the body fluids. When a faster setting bond is desired, abasic material can be used to accelerate polymerization of the monomer.Such basic materials can be amines, alcohols or the like.

The esters of a-cyanoacrylic acid can be used alone or blended withminor amounts of additives such as thickening agents, plasticizers,antibiotics or the like. The use of mixtures of the higher esters isalso within the scope of the invention. Of course, the materials mixedwith the a-cyanoacrylate ester must not cause the monomeric ester topolymerize prematurely and must not have an adverse effect on thehealing process.

Examples of suitable thickening agents or viscosity modifiers for suchcompositions include various polymeric or resinous materials such aspoly(alkyl 2- cyanoacrylates), poly(acrylates), poly(methacrylates),cellulose esters such as cellulose acetate, cellulose butyrate,cellulose acetate phthalate and the like, etc., the polymers of alkyl2-cyanoacrylates being preferred. Typical of the suitable plasticizersare dimethyl sebacate, di-n-butyl sebacate, di-n-octyl phthalate,triethyl phosphate, triisobutyl phosphate, tri(2-ethylhexyl) phosphate,tri-p-cresyl phosphate, glyceryl triacetate, glyceryl tributyrate.diethyl sebacate and other plasticizer esters of the types disclosed inthe patent to Joyner and Coover, U.S. Pat. No. 2,784,127.

In the compositions containing additives, the a-cyanoacrylate monomer isthe major component and preferably is at least about weight percent ofthe composition. These compositions can contain up to about 20 percentby weight, based on the a-cyanoacrylate monomer, of the describedpolymeric thickening agent or viscosity modifier and up to about 20percent by weight based on the monomer of the described plasticizers.Preferably, for rapid adhesive action the amount of plasticizer is about1 to 5 percent by weight based on the monomer. in this preferred rangethe ester plasticizers improve the flexibility of the adhesive bondwithout adversely affecting the adhesive qualities of thea--cyanoacrylate.

As we have indicated, a catalyst or accelerator can be used to obtain amore rapid bond. However, the catalyst would not be added to thea-cyanoacrylic acid ester any substantial length of time before thesurgical use because it would cause the monomer to polymerizeprematurely. The catalysts are normally used by application to thesurfaces of the tissues to be bonded. The adhesive monomer is applied tothe same or to the other surface and the two surfaces are promptlybrought together and held in place until a bond is formed. Normally,this requires only a few seconds. Suitable polymerization catalysts oraccelerators are those that have no adverse affect on the tissues beingtreated and include suitable solutions of aliphatic alcohols such asmethanol, isobutanol, capryl alcohol, etc; and of such basic materialsas ammonia, piperidine, pyridine, etc.

While the higher esters of a-cyanoacrylic acid have reasonably goodstability as monomers when stored in bulk, especially when the estersare of high purity, polymerization inhibitors can be used to increasethe storage stability. Suitable inhibitors or stabilizers that can beused in small amounts, e.g., 0.0001 to 0.01 weight percent, includesulfur dioxide, hydroquinone, nitric oxide, organic acids, etc. Thepreferred stabilizers are those having the least adverse physiologicalafi'ect.

Our work has indicated that the biological utility of thea-cyanoacrylate monomers is not directly related to their effectivenessin joining together inanimate objects. In the series of esters ofalltanols of 2 to carbon atoms there appears to be an increasingeffectiveness in rapid formation of strong, firm bonds with an increasein length of the alkyl chain of the alcohol moiety of the ester,although this may be accompanied by some increase in temporaryirritation, at least with the capryl ester. The isobutyl ester isparticularly outstanding. The bonds formed from it are strong, thewounds heal promptly, there is little irritation from the monomer andthe bonds are more flexible than the bonds formed with other esters.

The adhesive compositions used in the method of the invention formstrong bonds with all types of human and animal tissues. The bonds arestrongest when a minimal amount of adhesive is applied. This makes itpossible for the normal fibroblasts and other cellular elements ofhealing to penetrate rapidly through the bond where necessary to permitthe natural healing process to take place. As we have indicated, theslightly alkaline pH of the body fluids act as a natural catalyst to thepolymerization of the monomer. Some body fluids interfere with theformation of the bond and must be controlled. Another difficulty thatcan be encountered is in eliminating contact of the adhesive with tissueunderlying the tissue that it is desired to bond. Such contact can causeadhesions to form that make an undesirable wound closure. We mentionthese difficulties merely to show that when using an adhesive forsurgical purposes skillful manipulation is required for best results.Despite these difficulties the fact remains that the higher esters ofa-cyanoacrylic acid provide a valuable new means for achieving surgicalbonding.

The practice of the method of the invention is further illustrated bythe examples hereinafter.

In the examples employing guinea pigs the general procedure was that theguinea pigs were immobilized, a local anesthetic was injected into alarge area of the back and lateral incisions of about 2 to 4 centimeterswere made across the mid-back region. Full thickness incisions were madeand the wounds gaped with a moderate amount of bleeding. The blood wassponged and hemostats were used to control further bleeding. Afterbleeding had stopped or was minimal the adhesive composition was drawninto a capillary tube and excessive quantities were applied to bothsurfaces of the skin from the capillary tube. Excess adhesive wasquickly wiped off and the two edges were lightly pinched together untilthey adhered. Normally in these tests the skin was swabbed with percentethanol. The instruments were clean, though not necessarily sterile. Themonomeric esters are sterile as produced and do not permit growth oforganisms with which they may be contacted accidentally. No frankinfections were noted in the experimental animals.

EXAMPLE 1 Using the above general procedure the monomer, isobutyl2-cyanoacrylate, was successfully used on three guinea pigs to seal afull thickness incision 1 inch in length. Immediate polymerization andfirm closure were observed. The results were substantially better thanobtained with methyl Z-cyanoacrylate with respect to immediate andstrong closure of the incision. The incisions healed rapidly. It appearsthat the polymer was removed from the wound area during the healingperiod at a satisfactory rate. Good fibroblastic response was noted.There was little evidence of any foreign body reaction. The epitheliumcompletely healed over the area. The bonds were substantially lessbrittle than those formed with methyl 2-cyanoacrylate, both immediatelyafter incision and in the course of the next few days.

EXAMPLE 2 In the manner of Example 1, capryl a-cyanoacrylate was usedfor adhesive bonding of incisions on five guinea pigs, and immediatefirm bonds formed in each test. The wounds appeared to heal normally.During the first 24 hours following application there was some what moreswelling of the tissue than was observed with isobutyl wcyanoacrylate.However, this swelling was temporary. Subcutaneous injections of thecapryl a-cyanoacrylate have shown no unusual inflammatory reaction.

EXAMPLE 3 A monomeric sample of isobutyl 2-cyanoacrylate was used toclose a 3-inch incision in a mongrel dog. The sides of the incision wereheld in place while the adhesive was applied with a sterile brush. Afterthe monomer had polymerized, it was observed that the edges of theincision were perfectly matched and that the incision was covered andprotected by a flexible, waterresistant film which did not restrictnormal movements of the injured animal. After a period of several days,

the incision had healed completely with only a very fine scar beingproduced. The use of monomeric cyclohexyl Z-cyanoacrylate as an adhesivein the same manner produced similar good results.

EXAMPLE 4 In this experiment, monomeric n-butyl 2- cyanoacrylatethickened with 5 percent by weight of a poly(n-butyl 2-cyanoacrylate)was used to suture an incision on the stomach of a guinea pig. The areaaround the incision was moistened with an ethanol solution of novocainewhich serves two functions: 1. to anesthesize the area, and 2. topromote the bonding action of the adhesive. The n-butyl Z-cyanoacrylateadhesive was painted over the incision with a small artists brush. Agood film over the wound was obtained by use of two coats of adhesive.After several days, the incision had healed neatly with only a fine scarbeing produced.

The invention has been described in considerable detail with particularreference to certain preferred embodiments thereof, but it will beunderstood that variations and modifications can be effected within thespirit and scope of the invention as described hereinabove, and asdefined in the appended claims.

We claim:

1. The method for surgical bonding of body tissues which comprisesapplying to at least one of the tissue surfaces to be bonded an adhesivecomposition comprising a monomeric ester of a-cyanoacrylic acid of theformula:

wherein R is a saturated hydrocarbon radical of 2 to carbon atoms,bringing together the surfaces to be bonded and polymerizing saidmonomeric in contact with such surfaces.

2. The method according to claim 1 in alkyl of 3 to 6 carbon atoms.

3. The method according to claim I in ester is isobutyl a-cyanoacrylate.

4. The method according to claim 2 in ester is pentyl a-cyanoacrylate.

5. The method according to claim 2 in ester is butyl a-cyanoacrylate.

6. The method according to claim 2 in ester is ethyl a-cyanoacrylate.

7. Surgical method which comprises applying to incisions or wounds inbody tissues an adhesive composition comprising a monomeric ester ofalphacyanoacrylic acid of the formula:

ester while which R is which said which said which said which saidwherein R is a saturated hydrocarbon radical of 2-10 carbon atoms, andpolymerizing said monomeric ester while it is in contact with said bodytissues and with body fluid seepage to form a protective bond with saidtissues.

8. The method according to claim 7 in which R is alkyl of 3 to 6 carbonatoms.

9. The method according to claim 7 in which said ester is isobutylalpha-cyanoacrylate.

10. The method according to claim 7 in which said ester is pentyla-cyanoacrylate.

11. The method according to claim 7 in which said ester is butyla-cyanoa'crylate.

12. The method according to claim 7 in which said ester is ethyla-cyanoacrylate.

* t 16! ll 0' UNITED STATES PATENT oEFlcE f CERTIFICATE OF CORRECTIONPatent No. 5,759,26 Dated September 18, 1975 In Harry W. Coover, Jr. eta1.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

. Column 1, between the title and line 1, please insert the following:

-- This application is a Stream lined Continuation of Serial No.225,896; filed September 2 T, 1962, now abandoned.

Signed" and sealed this 15th day of' October 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner ofPatents FORM Podoso (1069) I Y uscoMM-oc soars-ps9 us. GOVERNMENI rmmmsOFFICE 93o

2. The method according to claim 1 in which R is alkyl of 3 to 6 carbonatoms.
 3. The method according to claim 1 in which said ester isisobutyl Alpha -cyanoacrylate.
 4. The method according to claim 2 inwhich said ester is pentyl Alpha -cyanoacrylate.
 5. The method accordingto claim 2 in which said ester is butyl Alpha -cyanoacrylate.
 6. Themethod according to claim 2 in which said ester is ethyl Alpha-cyanoacrylate.
 7. Surgical method which comprises applying to incisionsor wounds in body tissues an adhesive composition comprising a monomericester of alpha-cyanoacrylic acid of the formula:
 8. The method accordingto claim 7 in which R is alkyl of 3 to 6 carbon atoms.
 9. The methodaccording to claim 7 in which said ester is isobutylalpha-cyanoacrylate.
 10. The method according to claim 7 in which saidester is pentyl Alpha -cyanoacrylate.
 11. The method according to claim7 in which said ester is butyl Alpha -cyanoacrylate.
 12. The methodaccording to claim 7 in which said ester is ethyl Alpha -cyanoacrylate.